The single pre-eminent objective of this proposal is to gain an understanding of how the constitution of the cell surface is involved in differentiation exemplified in embryogenesis, in environmental regulation of differentiated function, and in malignant transformation. This involves the joint and several applications of many disciplines and approaches. Cellular differentiation and proliferation are the central phenomena on which all our interests converge. In relating the genome to cell surface constitution, much is being learned from systematic immuno-genetic analysis of the surfaces of differentiated cells: applied to T-lymphocytes, findings of great value relating to immunology are forthcoming; applied to sperm, ova and embryonic cells, findings of equal relevance to reproductive biology are in the making. The insertion, mutual dispositions, migrations and turn-over, of the genetically specified elements of the cell surface, constitutes a second level of order and organization which may be termed 'Topography and Dynamics', and is represented in this application by increasingly precise technology. The nature of the interaction between environmental regulators and the cell surface is the subject of many sections in this application, and is clearly fundamental, because every differentiated cell must of necessity have undergone many such encounters, and continues to do so through its life-history. Questions relating to whether the apparatus comprised by the cell's outer membrane as a whole includes provision for internal control or synthesis independent of the genome are also addressed, as an essential corollary to inquiry into the circuitry linking external regulators with the genome, via transmitting mechanisms in the plasma membrane and cytoplasm. Analysis of the manifold functions of the cell surface demands that they should be broken down into a set of simplified experimental systems, exemplified in the proposal by collected projects on the induction of T-cell differentiation, the interactions of hormones with cell surface membranes or on the analysis of cyclic and noncyclic nucleotide messengers. This is our view of how the biology of the cell surface will come to be understood, in its normal operation, and in the breakdown of its functions in cancer.